The present invention relates to oral compositions and methods for inhibiting bone resorption in a mammal while counteracting potential adverse gastrointestinal effects. The compositions useful herein comprise the combination of a pharmaceutically effective amount of a nitrogen-containing bisphosphonate or a pharmaceutically-acceptable salt thereof and a pharmaceutically effective amount of an isoprenoid compound.
A variety of disorders in humans and other mammals involve or are associated with abnormal bone resorption. Such disorders include, but are not limited to, osteoporosis, Paget""s disease, periprosthetic bone loss or osteolysis, and hypercalcemia of malignancy. The most common of these disorders is osteoporosis, which in its most frequent manifestation occurs in postmenopausal women. Osteoporosis is a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporotic fractures are a major cause of morbidity and mortality in the elderly population. As many as 70% of women and a third of men will experience an osteoporotic fracture. A large segment of the older population already has low bone density and a high risk of fractures. There is a significant need to both prevent and treat osteoporosis and other conditions associated with bone resorption. Because osteoporosis, as well as other disorders associated with bone loss, are generally chronic conditions, it is believed that appropriate therapy will typically require chronic treatment.
Multinucleated cells called osteoclasts are responsible for causing bone loss through a process known as bone resorption. It is well known that bisphosphonates are selective inhibitors of osteoclastic bone resorption, making these compounds important therapeutic agents in the treatment or prevention of a variety of generalized or localized bone disorders caused by or associated with abnormal bone resorption. See H. Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To The Patient, 3rd Edition, Parthenon Publishing (1997), which is incorporated by reference herein in its entirety. Without being limited by theory, it is believed that bisphophonates inhibit osteoclast function by triggering apoptosis, i.e. programmed cell death. See D. E. Hughes et al., xe2x80x9cBisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivoxe2x80x9d, Journal of Bone and Mineral Research, 10 (10), 1478-1487, 1995, which is incorporated by reference herein in its entirety.
At present, a great amount of preclinical and clinical data exists for the potent aminobisphosphonate compound alendronate. Evidence suggests that other nitrogen-containing bisphosphonates such as pamidronate, risedronate, ibandronate and zolendronate, have many properties in common with alendronate, including high potency as inhibitors of osteoclastic bone resorption.
Despite their therapeutic benefits, bisphosphonates are poorly absorbed from the gastrointestinal tract. See B. J. Gertz et al., Clinical Pharmacology of Alendronate Sodium, Osteoporosis Int., Suppl. 3: S13-16 (1993) and B. J. Gertz et al., Studies of the oral bioavailability of alendronate, Clinical Pharmacology and Therapeutics, vol. 58, number 3, pp. 288-298 (September 1995), which are incorporated by reference herein in their entirety. Intravenous administration has been used to overcome this bioavailability problem. However, intravenous administration is costly and inconvenient, especially when the patient must be given an intravenous infusion lasting several hours on repeated occasions.
If oral administration of the bisphosphonate is desired, relatively high doses must be administered to compensate for the low bioavailability from the gastrointestinal tract. To offset this bioavailability problem, it is generally recommended that the patient take the bisphosphonate on an empty stomach and fast for at least 30 minutes afterwards. However, many patients find the need for such fasting on a daily basis to be inconvenient. Moreover, oral administration has been associated with adverse gastrointestinal effects, especially those relating to the esophagus. See Fleisch, Id. These effects appear to be related to the irritant potential of the bisphosphonate in the esophagus, a problem which is exacerbated by the presence of refluxed gastric acid. Without being limited by theory, it is believed that the potential gastrointestinal effects of oral bisphosphonates is related to the induction of apoptosis, i.e. programmed death, of the cells of the epithelial lining of the gastrointestinal tract.
For example, the bisphosphonate, pamidronate has been associated with esophageal ulcers. See E. G. Lufkin et al., Pamidronate: An Unrecognized Problem in Gastrointestinal Tolerability, Osteoporosis International, 4: 320-322 (1994), which is incorporated by reference herein in its entirety. Although not as common, the use of alendronate has been associated with esophagitis and/or esophageal ulcers. See P. C. De Groen, et al., Esophagitis Associated With The Use Of Alendronate, New England Journal of Medicine, vol. 335, no. 124, pp. 1016-1021 (1996), D. O. Castell, Pill Esophagitisxe2x80x94The Case of Alendronate, New England Journal of Medicine, vol. 335, no. 124, pp. 1058-1059 (1996), and U. A. Liberman et al., Esophagitis and Alendronate, New England Journal of Medicine, vol. 335, no. 124, pp. 1069-1070 (1996), which are incorporated by reference herein in their entirety. The degree of adverse gastrointestinal effects of bisphosphonates has been shown to increase with increasing dose. See C. H. Chestnut et al., Alendronate Treatment of the Postmenopausal Osteoporotic Woman: Effect of Multiple Dosages on Bone Mass and Bone Remodeling, The American Journal of Medicine, vol. 99, pp. 144-152, (August 1995), which is incorporated by reference herein in its entirety. Also, these adverse esophageal effects appear to be more prevalent in patients who do not take the bisphosphonate with an adequate amount of liquid or who lie down shortly after dosing, thereby increasing the chance for esophageal reflux.
Bisphosphonate treatment regimens normally involve the chronic administration of relatively low doses of the bisphosphonate compound, with the objective of delivering the desired cumulative therapeutic dose over the course of the treatment period. However, chronic dosing, especially chronic daily dosing, can have the disadvantage of causing adverse gastrointestinal effects due to the repetitive, continuous, and additive irritation to the gastrointestinal tract. This potential problem can therefore interfere with patient compliance, and in severe cases even require cessation of treatment. Therefore, it is seen that there is a need to minimize the potential adverse effects that can be associated with bisphosphonate bone resorption therapy.
Isoprenoids are compoounds that are constructed from the five-carbon building block isoprene, which is also known as 2-methyl-1,3-butadiene. Compounds comprising two or more isoprene units are known as terpenes. Examples of isoprenoids and terpenes include 3,3-dimethyl-2-butan- 1-ol (a five-carbon compound), geraniol (a ten-carbon compound), farnesol (a fifteen-carbon compound), and geranylgeraniol (a twenty-carbon compound). See Lehninger, A. L., Biochemistry, 1975, pp. 296, and 682-683, which is incorporated by reference herein in its entirety.
For example, geranylgeraniol is a linear terpene containing four isoprene units, corresponding to the following chemical structure. 
The geranylgeraniol derivative, geranylgeranyl pyrophosphate is an intermediate in the cholesterol biosynthetic pathway and is a substrate in the prenylation of proteins. See J. A. Glomset et., Geranylgeranylatedproteins, Biochem-Soc-Trans., 1992 May, 20(2): 479-484, which is incorporated by reference herein in its entirety.
It is found in the present invention that isoprenoids block the bisphosphonate-induced inhibition of osteoclast function. For example, in osteoclast cell cultures and bone resorption assays, isoprenoids such as geranylgeraniol can block the inhibitory effect that would otherwise be observed with a bisphosphonate such as alendronate monosodium trihydrate. In the osteoclasts, it is believed that nitrogen-containing bisphosphonates trigger the cleavage of a kinase known as Mst (mammalian Sterile-20-like kinase). At least two isoforms of Mst are known, i.e. xe2x80x9cMst 1xe2x80x9d and xe2x80x9cMst 2xe2x80x9d. See, Taylor et al., xe2x80x9cNewly identified stress-responsive protein kinases, Krs-1 and Krs-2xe2x80x9d, Proc. Natl. Acad. Sci. USA, Vol. 93 (1996), pp. 10099-10104; Creasy et al., xe2x80x9cCloning and characterization of a human protein kinase with homology to Ste20,xe2x80x9d The J. of Biological Chemistry, Vol. 270, No. 37 (1995), pp. 21695-21700; Creasy et al., xe2x80x9cCloning and characterization of a member of the MST subfamily of Ste20-like kinasesxe2x80x9d, Gene, Vol. 167 (1995), pp. 303-306; Creasy et al., xe2x80x9cThe Ste 20-like protein kinase, Mst 1, dimerizes and contains an inhibitory domainxe2x80x9d, The J. of Biological Chemistry, Vol. 271, No. 35 (1996), pp. 21049-21053; and Wang and Erikson, xe2x80x9cActivation of protein serine/threonine kinases p42, p63, and p87 in Rous sarcoma virus-transformed cells: signal transduction/transformation-dependent MBP kinasesxe2x80x9d, Mol. Biol. Cell, 3, pp. 1329-1337 (1992), which are all incorporated by reference herein in their entirety. Mst cleavage is known to be triggered by cellular stress events, and is associated with apoptosis. See Graves et al., EMBO Journal, 17, 2224-2234, 1998, which is incorporated by reference herein in its entirety. An isoprenoid such as geranylgeraniol, however, is found to prevent the cleavage of Mst that is induced by bisphosphonates such as alendronate monosodium trihydrate. However, isoprenoids have not previously been investigated either in vitro or in vivo for their ability to mitigate the potentially adverse gastrointestinal side effects that can be associated with bisphosphonate anti-bone resorption therapy.
In the present invention, the combination of a nitrogen-containing bisphosphonate or a pharmaceutically-acceptable salt thereof and an isoprenoid compound is highly effective for inhibiting bone resorption while mitigating the potentially adverse gastrointestinal effects that can be associated with bisphosphonate therapy. The combination has the advantage of providing increased safety and better patient compliance, which should maximize therapeutic efficacy. Without being limited by theory it is believed that the isoprenoid compound blocks the potentially harmful effect of the bisphosphonate on the epithelial cells of the gastrointestinal tract. By selecting an appropriate dosage of the isoprenoid compound it is possible to orally deliver a sufficiently high local concentration of the isoprenoid compound to the gastrointestinal tract to block the potentially harmful effects of the nitrogen-containing bisphosphonate, while minimizing the blocking effect on the osteoclasts, where the full therapeutic benefit of the bisphosphonate is desired to inhibit bone resorption.
It is an object of the present invention to provide compositions comprising the combination of a nitrogen-containing bisphosphonate or a pharmaceutically-acceptable salt thereof and an isoprenoid compound.
It is another object of the present invention to provide improved oral methods for inhibiting bone resorption and the conditions associated therewith in a mammal, particularly wherein said mammal is a human.
It is another object of the present invention to provide improved oral methods for treating or preventing abnormal bone resorption and the conditions associated therewith.
It is another object of the present invention to provide such oral methods while counteracting potential adverse gastrointestinal effects.
It is another object of the present invention to provide such methods wherein the dosing is maintained until the desired therapeutic effect is achieved.
It is another object of the present invention to treat or prevent abnormal bone resorption in an osteoporotic mammal, preferably an osteoporotic human.
These and other objects will become readily apparent from the detailed description which follows.
The present invention relates to a pharmaceutical composition comprising a nitrogen-containing bisphosphonate or pharmaceutically acceptable salt thereof and an isoprenoid compound.
In further embodiments the present invention relates to a pharmaceutical composition comprising a pharmaceutically-effective amount of a nitrogen-containing bisphosphonate or phamraceuticaliy acceptable salt thereof and an amount of an isoprenoid compound effective to counteract nitrogen-containing bisphosphonate-associated gastrointestional effects.
In further embodiments, the present invention relates to a method for inhibiting bone resorption in a mammal in need thereof comprising administering a nitrogen-containing bisphosphonate or pharmaceutically acceptable salt thereof and an isoprenoid compound.
In further embodiments, the present invention relates to a method for inhibiting bone resorption in a mammal in need thereof comprising sequentially administering an isoprenoid compound and a ntirogen-containing bisphosphonate or pharmaceutically acceptable salt thereof.
In further embodiments, the present invention relates to the use of a composition in the manufacture of a medicament for inhibiting bone resorption in a mammal in need thereof, said composition comprising a nitrogen-containing bisphosphonate or pharmaceutically acceptable salt thereof and an isoprenoid compound.
In further embodiments, the present invention relates to the use of a composition comprising a nitrogen-containing bisphosphonate or pharmaceutically acceptable salt thereof and an isoprenoid compound for inhibiting bone resoprtion in a mammal in need thereof.
All percentages and ratios used herein, unless otherwise indicated, are by weight. The invention hereof can comprise, consist of, or consist essentially of the essential as well as optional ingredients, components, and methods described herein.